Access and utilization of long chain fatty acyl-CoA by zDHHC protein acyltransferases

Abstract

S-acylation is a reversible posttranslational modification, where a long-chain fatty acid is attached to a protein through a thioester linkage. Being the most abundant form of lipidation in humans, a family of twenty-three human zDHHC integral membrane enzymes catalyze this reaction. Previous structures of the apo and lipid bound zDHHCs shed light into the molecular details of the active site and binding pocket. Here, we delve further into the details of fatty acyl-CoA recognition by zDHHC acyltransferases using insights from the recent structure. We additionally review indirect evidence that suggests acyl-CoAs do not diffuse freely in the cytosol, but are channeled into specific pathways, and comment on the suggested mechanisms for fatty acyl-CoA compartmentalization and intracellular transport, to finally speculate about the potential mechanisms that underlie fatty acyl-CoA delivery to zDHHC enzymes.

Figure 1.. Structure of palmitoyl CoA and enzymes that utilize it as a substrate.

(A) The two-step reaction catalyzed by zDHHC enzymes. (B) Structure of the precatalytic complex of human zDHHC20, with the zDHHC20 [9] shown in tan and palmitoyl CoA in aqua stick renditions. The positively charged residues in zDHHC20 that contact the charged CoA moiety are highlighted in green, Zn⁺² ions are shown as grey spheres. (C) Chemical structure of palmitoyl CoA illustrating its amphipathic character and the two different modules (please see text). (D) Structure of the complex of HHAT (lilac) [11] with palmitoyl CoA (aqua stick). The positively charged residues in HHAT that interact with the charged CoA moiety are rendered in green.

Figure 2.

Possible access modes for palmitoyl CoA to zDHHC enzymes and the bivalent mode of recognition of palmitoyl CoA by zDHHC20.

Figure 3.. Acyl CoA binding proteins and Acyl CoA synthetases.

(A) Structure of human acyl CoA binding protein [26] with myristoyl CoA. The protein is shown in lavender and myristoyl CoA in aqua. (B) Generic reaction catalyzed by the acyl CoA synthetase enzymes.